Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

Sachel Mok; Tomas Yeo; Davin Hong; Melanie J. Shears; Leila S. Ross; Kurt E. Ward; Satish K. Dhingra; Mariko Kanai; Jessica L. Bridgford; Abhai K. Tripathi; Godfree Mlambo; Anna Y. Burkhard; Megan R. Ansbro; Kate J. Fairhurst; Eva Gil-Iturbe; Heekuk Park; Felix D. Rozenberg; Jonathan Kim; Filippo Mancia; Rick M. Fairhurst; Matthias Quick; Anne Catrin Uhlemann; Photini Sinnis; David A. Fidock

doi:10.1126/SCIADV.ADI2364

Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

Sachel Mok, Tomas Yeo, Davin Hong, Melanie J. Shears, Leila S. Ross, Kurt E. Ward, Satish K. Dhingra, Mariko Kanai, Jessica L. Bridgford, Abhai K. Tripathi, Godfree Mlambo, Anna Y. Burkhard, Megan R. Ansbro, Kate J. Fairhurst, Eva Gil-Iturbe, Heekuk Park, Felix D. Rozenberg, Jonathan Kim, Filippo Mancia, Rick M. FairhurstMatthias Quick, Anne Catrin Uhlemann, Photini Sinnis, David A. Fidock

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

Abstract

Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian KEL1/PLA1 lineage. We mapped k13 as the central mediator of ART resistance in vitro and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping using 34 recombinant haplotypes, and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2/3 in mediating multigenic resistance to antimalarial agents.

Original language	English (US)
Article number	eadi2364
Journal	Science Advances
Volume	9
Issue number	45
DOIs	https://doi.org/10.1126/SCIADV.ADI2364
State	Published - Nov 10 2023

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Mok, S., Yeo, T., Hong, D., Shears, M. J., Ross, L. S., Ward, K. E., Dhingra, S. K., Kanai, M., Bridgford, J. L., Tripathi, A. K., Mlambo, G., Burkhard, A. Y., Ansbro, M. R., Fairhurst, K. J., Gil-Iturbe, E., Park, H., Rozenberg, F. D., Kim, J., Mancia, F., ... Fidock, D. A. (2023). Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness. Science Advances, 9(45), Article eadi2364. https://doi.org/10.1126/SCIADV.ADI2364

Mok, S, Yeo, T, Hong, D, Shears, MJ, Ross, LS, Ward, KE, Dhingra, SK, Kanai, M, Bridgford, JL, Tripathi, AK , Mlambo, G, Burkhard, AY, Ansbro, MR, Fairhurst, KJ, Gil-Iturbe, E, Park, H, Rozenberg, FD, Kim, J, Mancia, F, Fairhurst, RM, Quick, M, Uhlemann, AC, Sinnis, P & Fidock, DA 2023, 'Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness', Science Advances, vol. 9, no. 45, eadi2364. https://doi.org/10.1126/SCIADV.ADI2364

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title = "Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness",

abstract = "Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian KEL1/PLA1 lineage. We mapped k13 as the central mediator of ART resistance in vitro and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping using 34 recombinant haplotypes, and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2/3 in mediating multigenic resistance to antimalarial agents.",

author = "Sachel Mok and Tomas Yeo and Davin Hong and Shears, {Melanie J.} and Ross, {Leila S.} and Ward, {Kurt E.} and Dhingra, {Satish K.} and Mariko Kanai and Bridgford, {Jessica L.} and Tripathi, {Abhai K.} and Godfree Mlambo and Burkhard, {Anna Y.} and Ansbro, {Megan R.} and Fairhurst, {Kate J.} and Eva Gil-Iturbe and Heekuk Park and Rozenberg, {Felix D.} and Jonathan Kim and Filippo Mancia and Fairhurst, {Rick M.} and Matthias Quick and Uhlemann, {Anne Catrin} and Photini Sinnis and Fidock, {David A.}",

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doi = "10.1126/SCIADV.ADI2364",

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AU - Mok, Sachel

AU - Yeo, Tomas

AU - Hong, Davin

AU - Shears, Melanie J.

AU - Ross, Leila S.

AU - Ward, Kurt E.

AU - Dhingra, Satish K.

AU - Kanai, Mariko

AU - Bridgford, Jessica L.

AU - Tripathi, Abhai K.

AU - Mlambo, Godfree

AU - Burkhard, Anna Y.

AU - Ansbro, Megan R.

AU - Fairhurst, Kate J.

AU - Gil-Iturbe, Eva

AU - Park, Heekuk

AU - Rozenberg, Felix D.

AU - Kim, Jonathan

AU - Mancia, Filippo

AU - Fairhurst, Rick M.

AU - Quick, Matthias

AU - Uhlemann, Anne Catrin

AU - Sinnis, Photini

AU - Fidock, David A.

PY - 2023/11/10

Y1 - 2023/11/10

N2 - Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian KEL1/PLA1 lineage. We mapped k13 as the central mediator of ART resistance in vitro and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping using 34 recombinant haplotypes, and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2/3 in mediating multigenic resistance to antimalarial agents.

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Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness

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